Complexes of phosphanilic acid and 9-amino-3-nitroacridine useful as antifungal or antibacterial agents

ABSTRACT

Complexes of phosphanilic acid and an aminoacridine possess broad-spectrum antibacterial and antifungal activity when used topically. The preferred complex is a 1:1 complex of phosphanilic acid and 9-amino-3-nitroacridine.

United States Patent 1 1111 3,794,723

'Pagano 1 Feb. 26, 1974 [56] References Cited [54] COMPLEXES OF PHOSPHANILIC ACID 2,605,280 7/1952 Klotz 260/5025 AND 9 AMINO 3 NITROACRIDINE USEFUL 3,346,579 10/1967 Sheehan 3,442,938 5/1969 Christensen ct al. As ANTKFUNGAL 0R ANTIBACTERIAL 3,|22,553 2/1964 Seneca AGEN 2,245,539 6/1941 'Warnat 260/279 [75] Inventor: Joseph F. Pagano, Paoli, Pa [73] Assignee: sn ithklineCorporation, Primary Examiner Albert Meygrs Ph'ladelph'a 4 Assistant Examiner-Allen J. Robinson 22 Filed; Aug 9, 1972 Attorney, Agent, or FirmAlan D. Lourie; William H.

Edgerton [21] Appl. No.: 278,917

Related US. Application Data [62] Division of Ser. No. 18,312, March 10, 1970, Pat.

No. 3,694,447. ABSTRACT [52] US. Cl 424/200, 252/107, 424/211 Complexes of phosphanilic acid and an aminoacridine [51 Int. Cl. A01n 9/36 possess broad-spectrum antibacterial and antifungal [58] F i eici of Seai' ch... ..4 24/200, 21 11 260/2791, activity when used topically The Preferred 601111316X i 424/5025 a 1:1 complex of phosphanilic acid and 9-amino-3- nitroacridine.

UNITED STATES PATENTS 9 Claims, N0 Drawings 2,092,131 7/1937 Mietzsch..... 260/279.

l COMPLEXES OF Pl-IOSPHANILIC ACID AND 9-AMINO-3-NITROACRIDINE USEFUL AS ANTIFUNGAL OR ANTIBACTERIAL AGENTS This is a division of. application Ser. No. 18,312, filed Mar. 10, 1970, now U. S. Pat. No. 3,694,447 issued 9-26- 72.

This invention relates to compositions having antibacterial activity. In particular, the invention relates to complexes of phosphanilic acid and an acridine compound.

This invention, in its broadest aspect, comprises complexes of phosphanilic acid and an antibacterial acribeing N11,, and each R is hydrogen, amino, methyl, ethyl, methoxy, ethoxy, chloro, bromo, nitro, cyano, or phenyl.

The invention, in its preferred aspect, comprises the 1:1 and 2:1 complexes of phosphanilic acid and 9-amino-3-nitroacridine (111).

NHz

The complexes of this invention areprepared by mixing together pure samples of phosphanilic acid and the desired acridine. Complex formulation is most conveniently achieved by adding a hot solution of the phosphanilic acid to a warmed solution of the acridine. Hot water is thenadded with stirring, the mixture is eool ed and the product filtered off, washed, and dried. Warm or hot dimethyl sulfoxide is the preferred solvent, although other appropriate solvents, possibly including dimethylformamide, tetramethylene sulfone, or hexamethyl phosphoramide, may be used. Choice of appropriate solvents is well within the skill of the art. Generally, use of slightly more thantwo equivalents of phosphanilic acid in reaction with an aminoacridine will result in a 2:1 complex containing two equivalents of phosphanilic acid per equivalent of aminoacridine. Use of one equivalent will yield a 1:1 complex.

The complexes of the invention are active against a wide variety of microorganisms, including Grampositive bacteria, Gram-negative bacteria, and fungi. This activity is demonstrated for the preferred comln this system, the test compound is incorporated in agar at two-fold levels from 200 Lg/ml downward, and the test organisms inoculated onto the hardened agar surface. Activity is measured as the lowest concentration which prevents growth of the test organism. Results are shown in Table 1.

TABLE 1 IN VITRO ACTIVITY OF SK&F 36387-1 and SK&F 36387-1 Average MlC #g/ml (Range) S K&F 36287 SK&F 36387-1 Organism Staphylococcus ailreus 15.6 26.1

(6 strains) (6.3 25) (12.5 Slaphylncnccus alhus 8.2 8.6 (4 strains) (4.7 12.5) (6.3 12,5) Strep/04mins faecalis (l strain) 6.3 12.5 Slreplowccur pyogenes 7.6 15.3

(4 strains) (0.8 12.5) (1.6 25) Klehsiella pneumuniae 9.4 22.9

(3 strains) (3.1 12.5) (6.3 37.5) Escherichia mli 6.3 7.5

(5 strains) (6.3) (6.3 9.4) Salmonella .s'p. 14.6 25

(3 strains) (12.5 18.8) (25) S/iigella sp.

(1 strain) 3.1 3.1 Candida ulhic'ans 15.0 25.0 (5 strains) 25) (25) Pseuduimmas .rp. 5.1 g 7.1

(21 strains) plexes of the invention, the 1:1 complex of phos- 3 TA BLE 1 --Continued IN VITRO ACTIVITY OF SKdLF 36337-1 and SKALF 36387-J Average MIC ag/ml (Range) SK&F 36287-1 (1:1)

Organism SK&F 36387-1 Fungi: Fusnrium nxyspurum Pcnicillium cilrinum 6.8

(3.1 12.5) Aspergillus niger Crypmcoccus neufnrmans Blastomyccs dermuritidis Triclmphylon menlagmphy'res highly regarded commercial topical agents, hexachlomihefieliid nitrofurazone.

inadditi nto theZbBVeT a fiti ililution test was Ea?- ried out against 6 strains of Proteus sp., a Gramncgativc organism which frequently appears in burn cases and in mixed infections.

Results of these experiments are detailed in Tables 2, 3, 4, 5, and 6.

TABLE 2 IN VITRO ACTIVITY AGAINST GRAM POSITIVE BACTERIA (AGAR INCLUSION METHOD) Minimum Inhibitory Conc. #g/mI SK&F Orgamism 36387-1 Hexachlorophene Nitrofurazine Staphylococcus sp.

H.H. 06992 25 50 25 H.H. 06976 12.5 12.5 25 H.H. 06914 12.5 12.5 25 H.H. 06864 12.5 12.5 25 H.H. 07805 6.25 12.5 25 H.H. 06530 6.25 12.5 25 H.H. 49u 6.25 12.5 12.5 H,H. 07091 6.25 12.5 12.5 H.H. 30080 12.5 12.5 25 H.H. 30007 12.5 12.5 25 H.H. 30032 12.5 12.5 25 H.H. 29916 12.5 12.5 25 H.H. 29738 12.5 12.5 25 H.H. 29670 12.5 12.5 25 H.H. 30197 9.38 12.5 25 H.H. 30269 9.38 12.5 25

Average Staphylococcus sp.MIC

(16 strains) 113 14.8 23.4

Slrepmcvccus pyogenes H.H.514 12.5 25 I00 H.H. 238 3.12. 12.5 25 H.H. 151 0.78 12.5 4.7 H.H. 07208 0.4 12.5 25 H.H. 07477 0.4 12.5 3.12 Average Streptococcus pyogenes MIC (5 strains) 3.4 15.0 31.6

Average Gram-positive MIC 9.4 14.8 25.4

BIJEWZL IN VITRO ACTIVITY AGAINST GRAM-NEGATIVE BACTERIA (AGAR INCLUSION METHOD) Minimum Inhibitory Conc. JmI

SK&F Orgamism 36387-1 Hexachlorophene Nilrofurazone Escherichia culi H.H. 01428 6.25 100 9.4 H H. 01629 6.25 100 6.25 H H. 01668 6.25 100 4.7 H.H. 01694 6.25 100 6.25 H.H. 20206 6.25 100 12.5 H H. 20203 3.12 100 6.25 H H. 20201 6.25 100 25 H.H. 20187 6.25 100 25 H.H. 20170 6.25 100 12.5

Average E. coli MIC 5.9 100 11.9

(9 strains) Klebsiella pneumoniae H.H. 01482 18.8 100 2.5 H.H. 01607 12.5 200 25 H.H. 19938 18.8 100 25 H.H. 19895 18.8 100 25 Average K. pneumoniae MIC '4 strains) 17.2 12s 25 Salmonella sp.

H.H.94 25 100 12.5 H.H. 96 12.5 200 6.25 Shigella Sp.

H.H. 109 I 3.12 50 4.7 Average 'Salmonella/ ShigeIIa MIC 13 strains) 13.5 116.6 7.8

Average Gram-negative MIC 10.2 109.4 14.5

TABLE 4 V IN VITRO ACTIVITY AGAINST PSEUDOMONAS SP.

' (AGAR INCLUSION METHOD) Minimum Inhibitory Conc. #gImI SK&F Organism 36387-J Hexachlorophene Nitrofurazone Pseudomonas sp.

H.H. 12 6.3 150 200 H.Hf 38 12.5 200 200 H.H. 56 18.8 100 200 H.H. 63 6.3 100 200 H.H. 1879 6.3 100 200 H.H. 6835 12.5 100 200 H.H. 06910 25 150 200 H.H. 6962 3.1 100 200 H.H. 7180 12.5 100 200 H.H. 07070 6.3 100 200 H.H. 07167 18.8 150 200 ATCC 19660 3.1 75 200 H.H. 22074 25 75 200 H.H. 22106 6.3 75 200 H.H. 22167 9.4 100 200 H.H. 22179 18.8 100 200 H.H. 22863 2.3 100 200 H.H. 22869 12.5 75 200 H.H. 29628 3.1 100 200 H.H. 29621 3.1 100 200 H.H. 29334 1.6 100 200 H.H. 29322 3.1 100 200 H.H. 29310 6.3 100 200 H.H. 29260 6.3 100 200 H.H. 29156 6.3 100 200 H.H. 29674 6.3 100 200 H.H. 29107 6.3 100 200 H.H. 29080 9.4 100 200 H.H. 29063 9.4 100 200 2335,8A M 2.QQ

- k TABLE 4 -Conti nued IN VITRO ACTIVITY AGAINST PSEUDOMONAS SP.

(AGAR INCLUSION METHOD) Minimum Inhibitory Conc. ug/ml IN VITRO ACTIVITY AGAINST FUNGI (AGAR INCLUSION METHOD) Minimum Inhibitory Conc. #g/ml SK&F Organism 36387-J Hexachlorophene Nitrofurazone Candida alhiruns H.H. 95222 6.25 511 200 TrIt'/mph \'hm menIagruplrvlcs SKKLF 17410 1.17 12.5 100 PeniciI/um (i/film!" ATCC 16040 6.25 25 200 Aspergillus niger SK&F 330 9.38 25 W 200 Average Fungus MIC (3 strains) 9.10 45.3 I37.5

TABLE 6 i g A l ACTIVITY OF SK&F 36387-1, HEXACHLOROPHENE AND NITROFURAZONE AGAINST CLINICAL PROTEUS SPECIES Minimum Inhibitory Conc. ug/ml SK&F Proteus sp. 36387-1 Hexachlorophene Nitrofurazone Average Proteus sp. MIC 11.9 37.5 58.3

60 A n a ntirnicrobialagent, to be effective invivo, must The results show tlia t ot hcdrnplexes possess broad spectrum activity against all strains tested and, in particular, the 1:1 complex (SK&F- 36387-J) was effective against 40 hospital strains of Pseudomonas sp. and various clinical strains of Proteus sp. In contrast, hexachlorophene showed poor activity against Gramnegative organisms and nitrofurazone was ineffective against all strains of Pseudomonas and fungi tested.

be capable of retaining its activity in the presence of a variety of substances, including whole blood, serum, sebum, pus, and other body fluids. In addition, a topical antimicrobial intended for human use must also remain effective when applied to skin which retains traces of soap.

In vitro experiments were carrried out to evaluate the any in vitro test conditions, including medium containing no neutralizing substances.

The substantivity Tia com ound, eras ability to be retained by the cells of the skin, is a valuable characteristic for topical agents. Hexachlorophenes ability to do so is well known and serves as one of its major attractions, offsetting its limited spectrum of activity. Experi- EFFECT OF NEUTRALIZING SUBSTANCES ON ANTIBACTERIAL ACTIVITY Effect of Neutralizer on MIC* Test Compound Organism Soap Milk Serum Staph.

aureus FDA 209 l.4X l.5 2 SK&F 363 87-] Pseudomonas sp. HH I879 Il 2X 2X Staph.

aureus FDA 209 IX 4.5X 250X Hexuchlomphene Pseudomonas sp. HH I879 4x 64X l28x Staph. aureus Nitrofurazone FDA 209 0.5X IX 2X Pseudomonas Not Active No! Active Not active sp. HH I879 at I000 at I000 at I000 pg/ml. ,ug/ml. pg/ml.

Expressed in multiples of MIC in normal broth (no ncutralizcr added).

The results Show that SK&F 36387-.] is able to retain antimicrobial activity in the presence of neutralizing substances. In media containing percent serum and 5 percent milk (representative of organic and lipid materials), loss of activity was very slight. In the presence of soap, the anti-Pseudomonas activity of SK&F 36387- J was reduced moderately, but its anti-Staphylococcus activity suffered little. Hexachlorophenes activity in the presence of soap diminished slightly. In the presence of milk, loss of antibacterial activity became greater, and in the presence of 20 percent serum, activity loss was very severe, with MICs ranging from l28 to greater than 250 the drug level found effective in normal medium. Nitrofurazone lost little of its activity against Staphylococcus in the presence of Se rum, milk, or soap. Against Pseudomonas, however, ni-' trofurazone displayed no activity at 1,000 pg/ml under ments were carried out to assess m"""'i'h Jr-Tie substantivity of SI(&F 36387-J, hexachlorophene and nitrofurazone using an in vitro method utilizing skin discs. In this system, standardized calf skin discs are immersed in solutions of drug for 30 minutes, then vigor- I ously washed in running water for extended period of time. Washed discs are then placed on agar surfaces inoculated with Staphylococcus aureus and Pseudomonas sp. for 30 minutes, after which the discs are removed and the plates incubated. A substantive compound is defined as one which is sufficiently retained by the calf skin discs to produce zones of inhibition, despite the vigorous washing. The results of these in vitro experiments are shown in Table 8. Data are expressed as the diameter of the zones of inhibition produced by washed calf skin discs after exposure to solutions of the test compounds.

Table s SUBSTANTIVITY TEST ZONES OF INHIBITION (mm.) PRODUCED BY WASHED CALF SKIN DISCS Staph aureus var Smith Pseudomonas sp. HH 1879 Test Wash time Wash time Compound Level 0 I hr. 2% hr. 0 l hr. 2% hr.

SK&F 0.05% 14.5 I3 I I 25 23 16.5 363874 0.2% 20 16 I4 40 27.5 24.5

Nitrofura- 0.05% l8.5 4 0 0 0 0 zone 0.2% 27 I L5 9 0 0 0 Hexuchloro- 0.05% 21.5 l3.5 13.5 0 0 0 phene 0.2% 22.5 20 I7 ll Very Very slight slight Average of two tests.

1 1 SK&F 36387-1 was found to be substantive at both determine if viable bacteria remained in tubes beyond 0.05 percent and 0.2 percent. Activity of the comthe 72 hour end points, despite the absence of any such pound against Staphylococcus aureus and Pseudomonas evidence, aliquots of each were transferred to complexsp. was still evident after wash cycles of up to 2-Vz free medium. After incubation, tubes were examined hours. Hexachlorophene also displayed substantivity at 5 for evidence of bacterial growth; if present, the action both high and low test levels after prolonged washing. of SK&F 36387-1 would then be known to be bacterio- Nitrofurazone remained substantive after maximum static; if absent, the drug action would be bactericidal. wash time only at its higher test level; substantivity at Results are shown in Table 9.

TABLE 9 EFFECTS OF PROLONGED INCUBATION ON SK&F 36387-1 END POINTS Minimum Inhibitory Conc. (MIC) SK&F 36387-1 ,ug/ml.)

Proteus Proteus Proteus Staph. Staph. albus sp. Morgani Morgani aureus HH 7905 Condition HH 15066 HH 55 HH 57 HH 205 24 hr. MIC 5.1 5.1 5.1 2.6 1.3 72 hr. MIC 10.3 10.3 5.1 5.1 5.1 Type of inhibition Cidal Cidal Cidal Cidal Cidal the lower test level was no longer evident when .disc The results show that the MICs changed only slightly wash time was extended to 2 hours. m V with prolonged incubation. Sub-culturing of aliquots from tubes beyond the 72 hours MIC produced no sign Antimicrobial agents can be shown to exert either of of viable organisms; the action of SK&F 36387-1 two types of effects on bacterial cells: a truly lethal, ir- 25 against b th G i i d Grammegative b reversible, action termed bactericidal, or a reversible teria i een t b b ctericidal, action in which the organism, rendered free of the D t i T bl 4 indi at the anti-pseudomonas agent, can again multiply, in which case it is termed activity of SK&F 36387-1, compared with that of hexabacteriostatic. To determine whether the activity of chlorophene and nitrofurazone. In further experiments, SK&F 36387-1 is bactericidal or bacteriostatic, the fol- 3O SK&F 36387-1 was compared with compounds welllowing experiment was carried out. Two-fold dilutions known for their anti-Pseudomonas properties and of SK&F 36387-1 in broth were inoculated with three therefore used for treatment of burns. These comstr in f Gr m-nega iv bacteria (P n two pounds were gentamicin sulfate, mafenide hydrochlostrains of Gram-positive bacteria (Staphylococcus). ride, and silver sulfadiazine. These compounds are all After 24 hours incubation the minimum inhibitory con- 35 reputed to be highly effective. Compounds were evalucentration (MIC) of SK&F 36387-1 was observed. Inated in an in vitro, agar-inclusion system for activity cubation was continued for an additional 48 hours against 40 hospital strains of Pseudomonas sp. Results (total 72 hours) and the end points again observed. T9 of these experiments are presented in Table 10.

TABLE 10 IN VITRO ACTIVITY AGAINST PSEUDOMONAS SP. (AGAR-INCLUSION METHOD) Minimum Inhibitory Conc. (pg/ml) Pseudomonas sp. SK&F Gentamicin Mafenide Strain 36387-1 (Base) Silver sulfadiazine (HCl) HH 29913 5 5 6.9 25 400 HH 29980 3.1 6.9 25 400 HH 29998 1.6 6.9 25 400 HH 28592 1.0 13.7 25 400 HH 29308 6.0 6.9 25 400 HH 28858-A 25 6.9 25 400 HH 28858-8 25 3.5 25 400 HH 28858-C 18.7 6.9 25 400 HH 29063 18.7 6.9 25 400 HH 29080 4.7 6.9 25 400 HH 29107 15.6 6.9 25 400 HH 22858 25 6.9 25 400 HH 29156 7.8 6.9 25 400 HH 29260 18.7 6.9 25 400 HH 29310 12.5 6.9 25 400 HH 29322 2.7 6.9 25 400 HH 29323 25 6.9 25 400 HH 29334 2.3 13.7 25 400 HH 29621 9.4 3.5 12.5 400 HH 29674 10.9 13.7 25 400 HH 29628 6.3 3.5 25 200 HH 29689 4.7 6.9 25 400 HH 29704 3.1 6.9 25 400 HH 29714 4.7 6.9 25 400 HH 221169 4.7 10.3 18.7 400 HH 29163-A 12.5 3.5 25 400 NH 29260 9.4 (1.) 12,5 400 HH 29270 6.3 10.3 12.5 400 HH 29790 2.3 6.9 12.5 400 HH 29830 4.7 3.5 12.5 400 HH 29897 1.6 13.7 12.5 300 v ABLE :QR F PW IN VITRO ACTIVITY AGAINST PSEUDOMONAS SP. (AGAR-lNCLUSlON METHOD) Minimum Inhibitory Conc. (pg/ml) Pseudomonas sp. SK&F Gentamicin Mafenide Strain 36387-J (Base) Silver sulfadiazine (HCl HH 22074 12.5 6.9 12.5 400 HH 22179 9.4 6.9 12.5 400 HH 22167 6.3 13.7 12.5 400 HH 22168 18.7 6.9 400 HH 22978 3.1 6.9 25 400 HH 22869 6.2 6.9 25 400 HH 22979 3.1 6.9 18.7 400 HH 56 12.5 400 ATCC 19660 NIH 180 3.1 400 Average Pseudomonas MlC (40 strains) 9.4 7.5 21.7 395 Average of 3 tests *(1) Average of two or more tests test levels 8x to l 6 x higher than the other compounds.

7 An additional experiment was conducted to determine the ability of SK&F 36387-1 to prolong the lifetimes of burned mice infected with Pseudomonas. Male, albino, Charles River mice (14-18 grams) were burned by immersing the tails of etherized animals in water at 70 C for 5 seconds. Inoculation with Pseudomonas aeruginosa (ATCC No. 19660, NIH No. 180) was carried out 2 hours later by dipping the burned tails in an 18 hour broth culture of the organism. The tails were then encased in soft latex tubing (three-sixteenths inch bore, one-sixteenth inch wall) which was stapled to theloose skin at the base of the tail with Michel wound clips. Five hours post-infection, a single application of the test ointment (approximately 1.0 ml) was injected into the sheath enclosing the tail and the end of the sheath closed with a size 00 cork to avoid ointment loss. Mice were observed daily for deaths during the entire 12 day duration of the test. Heart blood and the kidneys of mice which died were cultured for viable organisms; in all cases, Pseudomonas, was recovered, indicating a Pseudomonas septicemia. Results are shown in Table 50 The results indicate that SK&F 36387-1, in a 0.2 percent ointment, provided excellent protection against the Pseudomonas aeruginosa infection produced in burned mice. The protection provided by a single application was long lasting, with 90 percent of the animals still protected on the 12th day after treatment. Gentamicin ointment provided initial protection equal to that of SK&F 36387-J, but its protective effect decreased with time. Commercial nitrofurazone ointment (0.2 percent) was protective for the first few days of the test only; by the tests end, percent of the treated animals had died. Untreated, infected animals quickly succumbed to their Pseudomonas infections (77 percent died by day 3); the burn control animals (no infection) survived the test with only 4/40 deaths.

The complexes of the present invention are intended to be used topically. They are formulated for such use by combining them with appropriate topically acceptable carriers or vehicles and other materials to form antiseptic solutions, soaps, shampoos, lotions, ointments, creams, toothpaste, powders, mouthwashes, etc. Those skilled in the art of pharmaceutical chemistry will be able to formulate these compositions without extensive experimentation utilizing normal skills as well as the information provided in the following examples. A solution should contain about 0.01-0.10 percent of the complex. A topical ointment should contain about 0.025-0.5 percent of the complex.

The following examples are intended to illustrate the complexes and compositions of the present invention,

TABLE 11 TOPICAL CHEMOTHERAPY OF PSEUDOMONAS SEPTlCEMlA 1N BURNED MICE Oint- Concen- No. ment tration of Survivors Days post-infection Type Used Mice 0 l 2 3 4 5 6 7 8 9 10 ll 12 SK&F

36387-J 0.2% 30 100 100 97 97 97 97 93 93 93 90 90 90 Placebo 70 100 100 88 59 51 46 34 28 25 21 21 21 21 Nitrofurazone 0.2% 20 100 100 80 65 60 55 55 45 35 3O 30 3O Gentamicin 0.12% 30 I00 100 90 83 83 8O 73 67 63 60 60 60 None (IN- fection control) 100 100 54 23 l6 l5 l3 l2 9 9 9 8 8 Burn control 40 100 100 100 100 98 9| 90 90 90 90 90 9O 9O but are not t o Efis'irhi as limiting the scope thereof.

EXAMPLE 1 EXAMPLE 2 2:1 Complex of Phosphanilic Acid and 3-Nitro-9- aminoacridine To a warm solution of 42 g. (0.176 m.) of 3-nitro-9- aminoacridine in 450 ml. of dimethyl sulfoxide was added a hot solution of 68.5 g. (0.39 m.) of phosphanilic acid in 900 ml. of hot dimethyl sulfoxide. The dark solution was stirred vigorously while 5,600 ml. of hot water was rapidly added. The reaction mixture was cooled to about C. and the product separated by filtration, washed with water and dried in vacuo at 100 C. to give 98 g. (95 percent yield) of 3-nitro-9- aminoacridine, diphosphanilic acid complex.

EXAMPLE 3 1n the same manner as in Example 1, a slight excess of phosphanilic acid may be reacted with each of the following acridines to give the corresponding 1:1 com plexes.

v 9-aminoacridine 3-aminoacridine 3 ,9-diaminoacridine 3,6-diaminoacridine 4,9-diaminoacridine 3 ,7-diaminoacridine 9-amino-4-methylaeridine 9-aminol-methylacridine 9-amino-3-methylacridine 9-amino-2-methylacridine 9-amino-3-chloroacridine 9-amino-2-chloroacridine 9-amino-1-chloroacridine 9-amino-4-chloroacridine 3-amino-6-chloroacridine 3-amino-7-chloroacridine 1,6-diaminoacridine 2,6-diaminoacridine 1,9-diaminoacridine 2,9-diaminoacridine 9-amin0-2,4-dimethylacridine 9-amino-4,5-dimethylacridine 9-amino-4-ethylacridine 9-aminol-methoxyacridine 9-amino-2-methoxyacridine 9-amino-3-methoxyacridine 9-amino-4-methoxyacridine 9-aminol -chloroacridine 9-amino-2-chloroacridine 9-amino-3-chloroacridine 9-amino-4-chloroacridine 9-aminol -nitroacridine 9-amino-2-nitroacridine 9-amino-3-nitroacridine 9-amino-4-nitroacridine 9-amino-2-phenylacridine 9-amino-4-phenylacridine 9-amino-2-cyanoacridine 9-methylaminoacridine 9-amino-2-carbomethoxyacridine "siaarirszieaisamayiszaaia' 3-dimethylaminoacridine EXAMPLE 4 1n the same manner as in Example 2, a slight excess over 2 equivalents of phosphanilic acid may be reacted with 1 equivalent of each of the acridines named in Example 3 to give the corresponding 2:1 phosphanilic acid-acridine complexes.

EXAMPLE 5 Examples of suitable formulations of the complexes are as follows: Antiseptic solution 0.05 percent w/v solution of the 1:1 complex of phosphanilic acid and 9-amino-3-nitroacridine in 50 percent water-SO percent glycerin. Pure glycerin may also be used as solvent.

Topical ointment (water-washable, oil-in-water emulsion) White petrolatum 69.80

Topical suspension 1:] complex of phosphanilic acid and 9-Amino-3-nitmacridine 0.200 Light liquid petrolatum 1.500 Cetyl alcohol 2.400 Stearyl alcohol 3.000 Tween 60 (Polyoxycthylene sorbitan 0.630

monostearate) Span 6O (Sorbitan monostearate) 0.630 Glycerin 3.000 Thimerosal 0.002 Water q.s. ad

Other complexes from Examples 2, 3, and 4 may similarly be formulated into solutions, ointments, and suspensions.

I claim:

l. A topical antibacterial or antifungal composition comprising an antibacterially or antifungally effective amount of a 1:1 or 2:1 complex of phosphanilic acid and 9-amin0-3-nitroacridine and a topically acceptable carrier.

7. The composition of claim 3 in the form of a solution wherein the solvent is glycerin or a glycerin-water mixture.

8. The composition of claim 3 in the form of an ointment.

9. The composition of claim 3 in the form of an aqueous suspension. 

2. The composition of claim 1, in which the complex is a 1:1 complex.
 3. The composition of claim 1, in which the complex is a 2:1 complex.
 4. The composition of claim 2 in the form of a solution wherein the solvent is glycerin or a glycerin-water mixture.
 5. The composition of claim 2 in the form of an ointment.
 6. The composition of claim 2 in the form of an aqueous suspension.
 7. The composition of claim 3 in the form of a solution wherein the solvent is glycerin or a glycerin-water mixture.
 8. The composition of claim 3 in the form of an ointment.
 9. The composition of claim 3 in the form of an aqueous suspension. 